Injectable and 3d Extrusion Printable Hydrophilic Silicone-Based Hydrogel for Controlled Drug Release

The present application claims the priorities from the U.S. provisional patent application Ser. No. 63/644,461 filed May 8, 2024, and the disclosure of which is incorporated herein by reference in its entirety.

The present invention generally relates to the field of material science and additive manufacturing. More specifically, the present invention relates a composition and process of silicone-based hydrogel for ophthalmic drug delivery with stimuli responsiveness.

Over the past decade, three-dimensional (3D) printing has become a key technology in manufacturing, used across industries like automotive, aerospace, dentistry, soft robotics, and pharmaceuticals. In healthcare, it's rapidly advancing, enabling complex structures like skeletal scaffolds and hydrogel-based heart models. This method shows great potential in bioengineering, drug delivery, and medical devices.

There are various 3D printing methods, with inkjet, laser-assisted, and extrusion-based printing being the most common. Among them, extrusion-based printing, or direct ink writing (DIW), is widely used and allows hydrogels to be used as printing materials. Microextrusion-based (ME) 3D printing has gained greater popularity than other types of 3D printing because of its versatility and the flexibility to use a wide variety of inks with varying viscosities. The ink must be fluid enough to be extruded via a nozzle, yet solid enough to stay there on the support substrate once it's been printed. Maintaining shape accuracy in ME is difficult because of competing ink requirements, which are based on ink flow characteristics that address gravitational pull and surface energyl,2. Without a speedy fixing procedure, printed objects might collapse under the weight of gravity once they reach a particular height, which is in turn regulated by the viscoelastic qualities of the ink used in the printing process.

For extrusion-based 3D printing, the ink must meet several key criteria: it should have adequate viscosity to stay in the injector, flow easily under pressure during extrusion, maintain shape fidelity by retaining viscosity when in contact with the printing platform, and fix quickly to prevent the printed structure from collapsing. The combination of microextrusion printing and photocuring was first reported to print gelatin methacryloyl based hydrogel3. Gelatin and alginated based blend hydrogel were reported via ME printing method for scaffold fabrication4. These hydrogels were used for tissue engineering applications and sustained/controlled release platforms of therapeutic payloads.

Recent advancements in drug delivery systems using hydrogels have been significant, as reflected in the extensive body of published research. In particular, ocular drug delivery via hydrogels, such as drug-eluting contact lenses (CLs), has garnered increasing interest. These hydrogel-based devices are especially promising for delivering topical ophthalmic treatments. As of the contemporary report, CLs can increase drug bioavailability in the eye by at least 50% compared to conventional eye-drops suspensions (1-5%) 5. However, choosing an appropriate CLs material still is a big challenge where wetting and eye comfort of the patient are the most prioritized section. Hydrogel-based systems were once the most promising materials for CLs due to their higher water content, durability, and biocompatibility. However, their limited oxygen permeability hindered broader use. This issue was addressed by silicone materials, which are more elastic and oxygen-permeable, reducing hypoxia-related issues. However, silicone-based CLs can be less comfortable for sensitive eyes due to eye deposits and silicone intolerance. Moreover, when incorporating drug-eluting properties into contact lenses, silicone-based systems face significant drawbacks compared to hydrogels. One potential solution is to combine both inorganic and organic polymeric systems to address these challenges. For drug-eluting contact lenses, a key limitation is drug encapsulation, where the drug molecules are trapped within the gel matrices and released in a controlled, delayed manner.

Therefore, there is a need in the art for an improved material system for drug-eluting contact lenses that combines the best properties of both hydrogels and silicones.

The present invention addresses long-standing challenges in the field of ocular drug delivery, particularly the difficulty in achieving sustained release from contact lens-compatible materials that also exhibit adequate oxygen permeability, mechanical stability, and patient comfort.

In one aspect, the present invention provides an injectable, extrusion-printable, and biocompatible formulation for 3D printing of a drug-releasing hydrogel. The formulation includes an aqueous dispersion of cellulose nanocrystals (CNCs) in an amount effective to impart shear-thinning behavior and yield stress sufficient to prevent nozzle dripping during pauses in extrusion, a monomer mixture comprising acrylamide (AM) and 2-hydroxyethyl methacrylate (HEMA), wherein the AM to HEMA weight ratio is between 1:3 and 3:1, a crosslinker, a photoinitiator, and an amine-functionalized silicone elastomer (AS). The formulation undergoes in situ ultraviolet-induced polymerization to form a semi-interpenetrating polymer network hydrogel with a mesh size of 50 Å to 150 Å. The hydrogel exhibits a tan delta (tan δ) value of less than 0.1 under oscillatory shear, indicating high elasticity.

In one embodiment, the AS content is in a range of 0.1 wt % to 10 wt %, and the CNCs content is in a range of 5 wt % to 15 wt %, based on total formulation weight.

In one embodiment, the photoinitiator includes lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP), 2-hydroxy-4′-(2-hydroxyethoxy)-2-methylpropiophenone), 2,2′-Azobis [2-methyl-N-(2-hydroxyethyl) propionamide] or their combination thereof, or any water soluble photo-initiator. The % in the formulation will be different for different photoinitiator.

In one embodiment, the crosslinker includes N,N′-methylenebisacrylamide (MBA), or a combination thereof, or any water soluble divinylic acrylates. The % in the formulation will be different for different diacrylates.

In one embodiment, the formulation exhibits a shear-thinning behavior, characterized by a decrease in viscosity from 10Pa·s at a shear rate of 0.1 sto 0.1 Pa·s at a shear rate of 100 s.

In one embodiment, the formulation displays a yield stress of approximately 1.8 Pa to 2.7 Pa when tested in compression mode.

In one embodiment, the semi-interpenetrating polymer network hydrogel exhibits zero permanent deformation following cyclic compression loading, a diffusion exponent (n) in the range of 0.5 to 0.75 indicative of non-Fickian anomalous transport behavior, and tunable oxygen permeability and mesh size modulated by the content of the AS.

In one embodiment, the semi-interpenetrating polymer network hydrogel has a Young's modulus greater than 10 kPa and an ultimate compressive strength of at least 50 kPa.

In one embodiment, the semi-interpenetrating polymer network hydrogel maintains dimensional and structural stability after immersion in phosphate-buffered saline at 37° C. for at least 10 days, and wherein the drug encapsulated therein retains at least 90% of its original chemical integrity and ultraviolet absorbance profile after storage for at least one month.

In one embodiment, the semi-interpenetrating polymer network hydrogel adheres to the periphery of a contact lens without delamination, distortion, or optical interference, and the semi-interpenetrating polymer network hydrogel conforms to the curvature of the cornea or sclera under ambient conditions.

In another aspect, the present invention provides a 3D printing method for fabricating a structurally stable semi-interpenetrating polymer network hydrogel. The method includes dispersing cellulose nanocrystals (CNCs) in water to form a shear-thinning base fluid; mixing the shear-thinning base fluid with a monomer mixture, a crosslinker, a photoinitiator, and an amine-functionalized silicone elastomer to form a precursor ink complex; extruding the ink complex into a predefined pattern using a microextrusion-based 3D printer, and subjecting extruded predefined pattern to continuous ultraviolet irradiation at a wavelength of 365 nm for a duration of 5 to 10 seconds to initiate polymerization and form the structurally stable semi-interpenetrating polymer network hydrogel. Simultaneous ultraviolet exposure and extrusion are employed to achieve in situ gelation during layer-by-layer deposition.

In one embodiment, the method further includes incorporating a therapeutic agent into the ink complex. The therapeutic agent is selected from antibiotics, anti-inflammatory drugs, anti-glaucoma drugs, or a combination thereof.

In one embodiment, the structurally stable semi-interpenetrating polymer network hydrogel sustains drug release for at least 8 hours post-application.

In one embodiment, the structurally stable semi-interpenetrating polymer network hydrogel exhibits no permanent deformation after undergoing at least 10 cycles of 20% strain.

In one embodiment, the structurally stable semi-interpenetrating polymer network hydrogel is printed in annular patterns with diameters of at least 10 mm. The minimum diameter is constrained by the printing resolution, typically around 10 mm, while the maximum is limited only by the printer's capacity, which can be quite large. In essence, this formulation and extrusion-based method allow users to print annular patterns with diameters determined by the capabilities of their specific printer.

In another aspect, the present invention provides a drug delivery system comprising the semi-interpenetrating polymer network hydrogel of claimprinted on a substrate.

In one embodiment, the substrate includes contact lenses, ocular patches, corneal bandages, or biodegradable ocular films.

In one embodiment, the semi-interpenetrating polymer network hydrogel has an oxygen permeability that exceeds that of poly (HEMA)-based hydrogel lenses by at least 25%.

In one embodiment, the semi-interpenetrating polymer network hydrogel is printed in a manner that allows the hydrogel to be detached and re-adhered without delaminating or compromising its structural integrity.

The developed hydrogel is tested by rheometry, Fourier Transform Infrared Spectroscopy (FTIR), Scanning Electron Microscopy (SEM), water uptake and drug release. The hydrogel exhibits high shear modulus, high gel strength. The hydrophilic silicone-based soft biomaterial enables controlled drug delivery with tunable diffusion behavior and stable encapsulation of drugs.

To overcome these limitations, the present invention provides an injectable, 3D extrusion-printable and biocompatible hydrogel. The synergistic blend of amine-functionalized silicone elastomers and hydrophilic monomers, structured into a semi-interpenetrating polymer network (semi-IPN). This hybrid formulation is further enhanced by the incorporation of cellulose nanocrystals (CNCs), which impart desirable shear-thinning and yield stress properties, allowing for precise and stable 3D printing using a UV-assisted microextrusion process.

The hydrogel composition leverages a synergistic combination of hydrogel and silicone materials, enhancing wearer comfort, sustained drug release, and mechanical strength. Notably, the hybrid hydrogels exhibit zero permanent set under cyclic compression, demonstrating exceptional elasticity and shape retention-properties not seen in conventional contact lens-compatible materials. The drug release follows a non-Fickian anomalous transport mechanism enabled by a semi-IPN, preventing the burst release commonly found in traditional systems. SEM reveals a microporous structure with tunable mesh size and crosslink density, allowing precise control over diffusion rates and oxygen permeability-both critical for ocular compatibility. The hydrogels also exhibit excellent long-term stability in aqueous media (PBS), and UV-visible spectroscopy confirms that the encapsulated drug remains chemically intact, preserving therapeutic efficacy. Furthermore, the fabrication process is streamlined through a single-step UV-curing and 3D printing method, enabling on-demand customization of drug-loaded geometries and offering superior efficiency and reproducibility compared to the multi-step processes reported in existing literature.

These features enable spatially controlled, long-term drug delivery directly on ophthalmic substrates such as contact lenses, with retained structural fidelity and sustained therapeutic performance. Additionally, the simplified, one-step curing and printing process allows for scalable, customizable manufacturing suitable for clinical deployment.

While silicone elastomers have found widespread usage in the biomedical industry, 3D printing them has proven difficult due to the material's slow drying time, low viscosity, and hydrophobic properties.

In addition, traditional hydrogels offer biocompatibility and drug encapsulation capabilities but suffer from low oxygen transmissibility and poor mechanical resilience. Conversely, silicone-based elastomers provide excellent oxygen permeability but are typically hydrophobic, mechanically unstable in printed form, and incompatible with uniform drug release profiles.

Therefore, the present invention provides a novel injectable and 3D extrusion-printable hydrophilic silicone-based hydrogel, designed specifically for ophthalmic drug delivery. This hybrid material overcomes key limitations in current 3D-printed hydrogel systems by combining the mechanical flexibility and oxygen permeability of silicone elastomers with the biocompatibility and drug-retaining capacity of hydrophilic polymers, resulting in a semi-IPN with tunable diffusion characteristics and exceptional structural integrity.

In contrast to traditional hydrogel or silicone-based matrices, the present invention integrates amine-functionalized silicone with poly(acrylamide-co-2-hydroxyethyl methacrylate) (poly(AM-co-HEMA)) via UV-assisted microextrusion printing, forming a robust hydrogel system. The thixotropic properties of the ink, derived from CNCs, ensure both extrudability and structural fidelity during layer-by-layer deposition, while UV-initiated free radical polymerization provides rapid and effective in situ gelation.

The specific combination of each constituent material into a structurally resilient, shear-thinning, and printable hydrogel composition represents a significant advancement over the prior art. This hybrid material successfully merges the drug-retaining and biocompatible characteristics of hydrophilic polymers with the mechanical flexibility and oxygen permeability of silicone elastomers-features not previously achieved in a single hydrogel system compatible with extrusion-based 3D printing.

Unlike prior systems that suffer from either rapid collapse during extrusion or poor post-printing mechanical strength, this hybrid ink formulation exhibits shear-thinning behavior, rapid solidification, and high gel strength, confirmed through rheological analyses including frequency sweep, damping behavior (tan δ), and onset of rupture testing. These mechanical properties were found to be tunable based on the AM/HEMA ratio and AS concentration, allowing the tailoring of viscoelastic profiles to meet application-specific demands.

The silicone phase imparts high oxygen transmissibility and elastic recovery, while the polar copolymer network of poly(AM-co-HEMA) enables effective drug encapsulation and sustained release. CNCs act as rheological modifiers, imparting thixotropic behavior and enhancing shape fidelity during the printing process. The resulting hydrogel displays a tunable viscoelastic profile, with key parameters such as mesh size, elastic modulus, and drug diffusion rate directly controlled by varying the AM/HEMA ratio and AS concentration. Notably, rheological analysis demonstrates high shear modulus, zero compression set under cyclic loading, and non-Fickian anomalous diffusion-all indicative of superior mechanical and functional performance not predicted by the prior art.

The hydrogel is fabricated using a streamlined, one-step UV-assisted microextrusion printing process. This method represents a significant improvement in manufacturability compared to conventional multi-step protocols used in hydrogel or silicone-based drug delivery systems. The ink formulation exhibits shear-thinning behavior, making it highly suitable for layer-by-layer deposition during 3D printing, while the incorporation of CNCs ensures extrusion stability and structural fidelity. Upon deposition, rapid in situ gelation is triggered by UV-initiated free radical polymerization, eliminating the need for post-printing crosslinking or thermal curing.

Unlike traditional hydrogels such as gelatin-methacrylate (GelMA) or alginate, which often suffer from low mechanical strength, poor shape retention, and unpredictable drug diffusion, the present invention maintains high mechanical integrity and allows precision shaping of complex geometries. The entire process—from material extrusion to final curing—can be completed in a single, continuous step, offering enhanced scalability, reproducibility, and cost-efficiency for biomedical manufacturing.

An overview of the fabrication process for the hydrophilic silicone-based hydrogel is presented in. CNCs are used as thioxotropic agent forming physical gel in presence of water resulting shear thinning behaviour of the hybrid ink. As CNCs are produced sulphuric acid hydrolysis, it consists abundant negative charges throughout the surface. The CNCs regulate the rheological characteristics of the ink, making it possible to generate a yield stress adequate for the temporary fixation of an extrusion-printed layer.

In order to better understand how ink behaves during the various stages of printing, rheology measurements are carried out. To prevent ink dripping from the syringe during non-printing stages, ink viscosity must be sufficiently high at a low shear rate. But at the time of syringe piston movement, viscosity must decrease promptly to allow extrusion. The gelation occurs here by UV triggered free radical polymerisation where lithium phenyl-2,4,6,-trimethylbenzoyphosphinate (LAP) is the photo-dissociable initiator. At the initiation stage LAP produces free radicals followed by 1 vinylic polymerization of AM, HEMA, and N,N′-Methylenebisacrylamide (MBA). AS is the non-crosslinked phase here entrapped into the gel matrix forming semi-interpenetrating polymeric network system.

Referring to, shear thinning occurred in all the formulations with very subtle changes. For perfect gelation or printability, the channels of the constructs would be connected in a square shape, and the Pr value would be 1. The level of gelation of the ink was found to be higher the higher the Pr value. The degree to which the ink gelled was lower the lower the Pr value. ImageJ (National Institute of Health) software was used to measure the perimeter and area of interconnected channels in printed structures to figure out the Pr value of each combination of printing parameters. Many methods were used to determine whether or not an ink could be printed, including rheology, ink state evaluations at the needle tip, and the stability of the printed multilayer structure.

depicts the three possible gelation states for printed ink: under-gelation, proper-gelation, and over-gelation. Under-gelation printing results in droplet morphology at the nozzle tip and ink fusing at the cross site, making it impossible to produce a mechanically sound 3D construct. Nevertheless, when the ink was over-gelled, its s hape became readily fragmented, displaying uneven filaments and linked channels. The printability of ink G4 was found to be around 0.92, which is very close to value 1, and as would be expected, for direct ink writing technology.

depict the various printed structures made from the hybrid ink. All the structures showed intricate shapes without any flow of the extruded filaments which also support the printability of the hybrid inks.

A primary application of these hydrogels lies in ophthalmic drug delivery, specifically in the development of therapeutic contact lenses. The hybrid material can be printed directly onto or into contact lens substrates, particularly along the lens periphery, enabling patient-specific designs without compromising lens geometry or comfort. The hydrogel's strong adhesion to the lens surface, combined with its zero permanent set and sustained drug release properties, makes it uniquely suited for long-term ocular applications. For instance, contact lens integration is made feasible via precise printing of hydrogel structures along the lens periphery, achieving strong adhesion without distorting the CL geometry. This feature significantly broadens clinical utility, enabling patient-specific therapeutic contact lenses that sustain drug release over prolonged periods.

The semi-IPN structure enables tunable, non-Fickian diffusion kinetics, providing controlled and sustained delivery of therapeutic agents over extended durations. UV-visible spectroscopy confirms chemical stability of encapsulated drugs, ensuring consistent efficacy throughout the treatment period. These features significantly outperform prior systems that rely on burst release, bulk-loaded drug reservoirs, or incompatible silicone matrices.

For printing over CLs, initially a circular CAD model was drawn with matching the outer diameter of the contact lens (14.3 mm). Then the CL was taken from the lens solution followed by gentle soaking into delicate task wipers. After complete removal of surface water, the CL was placed onto a glass support followed by printing as mentioned earlier. After printing the printed-CL assembly was kept under UV-light (5V, 2A, 365 nm) for around 6 s and dismantled from the glass support. The printed CLs have been displayed in.

shows the FTIR spectrum of the synthesized hydrogel. The spectrum shows major absorption peak at the range of 3350-3281 cmwhich is due to the stretching vibration of hydroxyl groups present in HEMA and —NHgroups of silicone. Both the monomers AA and HEMA have chaparetric stretching absorption of —C═O at around 1714 cm. Another significant peak at around 2900 cmis also observed which is due to stretching vibration of aliphatic C—H bonds present in polymer chains. The confirmation of silicone phase is supported by their characteristic peaks in the range of 800-1100 cmwhich are due to the presence of Si—O—Si linkages.

is the histogram plot of the different physical parameters related to the synthesis. These synthesis variables i.e. equilibrium swelling ratio (ESR), gel %, and yield % are dependent on the monomer ratio and hydrophilic silicone content. The ESR is dependent over the polarity of the hydrogel. It is seen from the plot that the ESR values were decreasing when monomer ratios were changed. For G1, the ESR value was lowered significantly due to combinational effect of AS and lowering of AA content. But for G2, the ESR was increased due to presence of more amount of AA. For G3 to G5, the ESR values show a decreasing trend due to increase in AS content. As AS does not posses sufficient hydrophilicity, thus the water imbibition through the hydrogel network becomes limited. For the gel % and yield % data, monomer ratio affects slightly but AS concentration affects drastically. Normally gel % is getting higher when least amount of leachable fractions are present in the gel metrics in forms of oligomers and unreacted monomers. But with AS content, the arrest of the silicone macrochians affect very negligible leaching resulting improvement in gel %.